1. Field of the Invention
The present invention relates to a biodegradable copolymer. More specifically, the present invention relates to a biodegradable copolymer having trans-4-hydroxy-L-proline or its N-substituted derivative as one of its constituent units. The present invention also relates to a pharmaceutical composition comprising this copolymer and a therapeutically effective amount of drug.
2. Description of the Related Art
Numerous drugs have been discovered in the past either by synthesis or extraction from natural substances and so forth. These drugs are used as therapeutic drugs by being injected into the body (i.e., bodies of humans or animals) or orally administered, etc. However, even if these drugs are administered into the body, there are many cases in which they do not demonstrate the anticipated physiological activity. This is due to the facts that the drugs are, for example, inadequately absorbed from the digestive tract, the drugs are digested or excreted, the drugs have extremely poor stability in the blood even if they enter the blood, the drugs are immediately decomposed so that they do not reach the site of action where they are to demonstrate their physiological activity, or they are in an inadequate amount even if they reach that site. Thus, in order to demonstrate the maximum physiological activity of the drug so that it functions as a therapeutic drug that is beneficial to the body, it is necessary to optimize the amount of drug at the site of action as well as that timing by controlling the kinetics of the drug in the body, including absorption, distribution, metabolism and excretion. This type of technology is typically referred to as a drug delivery system (DDS).
Although there are various means of controlling the kinetics of drugs in the body as mentioned above, these can be broadly divided into two methods. The first method involves chemical modification of the drug itself. The second method involves forming a composition containing the unchanged drug and another substance, more specifically, a carrier, to control the kinetics of the drug dependent on this carrier.
Although the former method is effective and is used practically being referred to as a prodrug, as the drug itself is chemically modified, it is structurally different from the original drug. On the other hand, in the case of the latter method, as the drug itself is not changed in any manner, the system is simpler than the former method with respect to the form of the drug, which is identical to the original drug. Accordingly, this method has been attempted using many carriers.
Examples of such a carrier include molecular aggregates of molecules such as liposome, and macromolecules such as poly(lactic acid), poly(glycolic acid), phospholipid, albumin, gelatin and collagen. Particularly, extensive research has been conducted in the past with respect to macromolecules, and there are many examples of their practical use in various forms (see, for example, "Biodegradable Polymers as Drug Delivery Systems", M. Chastin and R. Langer ed., Marcel Dekker pub., 1990).
Pharmaceutical compositions comprising this type of drug and carrier are administered into the body for various purposes, in various forms and in various manners.
For example, in order to gradually release a drug having either systemic or localized action, after containing the drug in a carrier using a suitable method, the drug-containing carrier is formed into microparticles having a diameter of several tens of microns and injected either subcutaneously or intramuscularly. A given amount of the drug is then gradually released from the microparticles at the injection site so as to maintain the concentration of drug in the body constant for an extended period of time (normally within a range of about one week or more up to about one year). Alternatively, similar microgranules are injected into a joint so as to maintain the concentration of drug in the joint at a constant high level for an extended period of time.
In addition, after incorporating the drug in the carrier using a suitable method, the drug-containing carrier is formed into a pellet having a size of several millimeters or more, followed by subcutaneous or intramuscular administration by making an incision. After suturing the incision, a given amount of the drug is released from the pellet for an extended period of time, after which an incision is again made and the pellet is removed.
Moreover, other methods include the preparation of an oral vaccine by oral administration of the above-mentioned microparticles, followed by the uptake of said microparticles by mesenteric lymph tissue resulting in an immunological reaction for the purpose of vaccination. In addition, another method involves the preparation of a vaccine by nasal administration of similar microgranules followed by the uptake of said microgranules by respiratory lymph tissue.
In order for pharmaceutical compositions used for the purposes and by the methods described above to become effective and safe therapeutic drugs, the carrier itself is required to have the following properties:
(1) The carrier must be a substance having low toxicity and high biocompatibility that does not cause harmful reactions such as inflammations in the body when brought in contact with body tissue.
(2) The carrier must be able to control the release of drug from the pharmaceutical composition.
(3) It is desirable that the carrier itself be biodegradable so that it breaks down in the body and eliminated naturally.
(4) The degradation products of the carrier must also have low toxicity.
(5) The carrier must be able to be easily formed into a form suitable for administration to the body, and the formed product must have suitable mechanical strength for use as a pharmaceutical preparation and so forth.
Although numerous compounds have been synthesized and extracted from naturally occurring substances and attempted to be used as carriers having the above-mentioned properties, the majority of research has been conducted on poly(lactic acid), poly(glycolic acid) and poly(lactic-co-glycolic)acid. These substances are attracting considerable attention as the substances themselves are already being used as suture thread, and their safety has been verified.
As mentioned above, although poly(lactic acid), poly(glycolic acid) and poly(lactic-co-glycolic)acid are already being partially used practically as carriers of microgranular injection preparations functioning as biodegradable polymers, the properties of those carriers are not always satisfactory.
For example, as poly(lactic acid) and poly(glycolic acid) have a high degree of crystallinity and are non-water-soluble, they have a slow rate of hydrolysis, and it is also difficult to control the rate of that hydrolysis. In fact, in the case of administering pharmaceutical compositions of their polymers and drugs, for example, subcutaneously, the situation occurs in which only the polymer remains for an extended period of time at the administration site even after the drug has been released from said composition (Kimura, Kitao and Shirotani: "Kobunshi Kakoh (i.e., Macromolecule Processing)", 37(7), 327-334, 1988).
Several solutions have been proposed with respect to these problems. For example, a method has been proposed wherein polylactic acid is made easily degradable by forming it into a low molecular weight molecule having a molecular weight of about 2,000 (Japanese Unexamined Patent Publication No. 61-172813). However, this method has been indicated to have problems including poor moldability and difficulty in forming microparticles (or microcapsules).
On the other hand, poly(lactic-co-glycolic)acid have a low degree of crystal formation by virtue of their structure being that of a copolymer. As a result, the problems accompanied with the above-mentioned polylactic acid and polyglycolic acid are solved since the rate of hydrolysis is greater in comparison to that of said lactic acid and glycolic acid. However, when this copolymer is used as a drug carrier, although the completion of drug release and the elimination of the carrier can be coincided, a relatively large amount of drug is released initially (referred to as the "initial burst phenomenon"), after which the release rate decreases, whereby a continuous and effective constant release of drug into the body cannot be effected. It is known that this phenomenon is particularly remarkable in the case where the drug is a hydrophilic, water-soluble drug such as a peptide or protein (Japanese Unexamined Patent Publication No. 1-216917).
This initial burst phenomenon has an extremely significant effect on the body when the drug in question possesses considerable physiological activity. In other words, the greater the physiological activity of the drug, the more important it is to carefully control its concentration within the therapeutically effective range. Thus, methods for suppressing this initial burst phenomenon have been proposed not only for the above-mentioned poly(lactic-co-glycolic)acid, but also for numerous other biodegradable carriers.
For example, although Langer et al. proposed a biodegradable carrier having a constant release rate, or in other words, zero-order release, using polyanhydride (Journal of Polymer Science Part A, Vol. 25, 3373 (1987)), it has been indicated to have numerous problems that have prevented its practical use, including being difficult to handle due to its remarkably high solubility in water, it being unable to release the drug at a constant rate over a period of time of 1 month or more, and it being difficult to form into microcapsules due to its low mechanical strength.
In addition, although Choi et al. have proposed a biodegradable carrier having a constant release rate using polyorthoester (U.S. Pat. No. 4,093,709), it also has been indicated to have problems that prevented its practical use, including the requiring of an additive for control of the rate of hydrolysis, and it being unable to achieve zero-order release when the physiologically active substance is hydrophilic.
Moreover, although efforts have also been made in the past to use biomacromolecules such as collagen, gelatin and albumin as biodegradable carriers having zero-order release, these substances have been indicated to have problems such as the formation of antigenicity and difficulty in forming microcapsules.
In addition, although these methods have resulted in the proposal of carriers having new structures in order to suppress the above-mentioned initial burst phenomenon, there have also been proposals made stating that these problems can be solved even by using conventional lactic-acid-glycolic acid copolymers as is.
For example, a method has been reported, wherein zero-order release is possible by using gelatin gel for the internal aqueous phase when manufacturing microcapsules consisting of drug and a poly(lactic-co-glycolic)acid using immersion drying (Japanese Unexamined Patent Publication No. 62-201816). However, those drugs capable of achieving zero-order release with this method are said to be only LH-RH substances (Ogawa, et al.: International Journal or Pharmaceutics, 69, 69-75 (1991)), and as such, cannot be said to be a universal method that can be applied for numerous drugs. In addition, although a method for manufacturing a composition consisting of a drug derivative and poly(lactic-co-glycolic)acid has been reported in order to increase the interaction between the drug and the carrier (Japanese Unexamined Patent Publication No. 63-41416), this method is also not a universal method that can be applied to numerous drugs.
Thus, there is a need for a universal material that can be manufactured into a carrier that has a high degree of biocompatibility, is biodegradable, allows control of drug release by suppressing initial burst phenomenon in particular, can be formed into various types of administration forms, and allows the resulting formed product to have adequate mechanical strength. In particular, there is a need for poly(lactic acids), poly(glycolic acids) and poly(lactic-co-glycolic)acid that suppress initial burst phenomenon and allow control of drug release.